cardiovascular outcome trials(n=3) bari-2d accord vadt cardiovascular effects of rosiglitazone •...
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Cardiovascular Outcome Trials How is Benefit-Risk Appropriately
Balanced with Respect to
Cardiovascular Outcomes?
Sanjay Kaul, MD, FACC, FAHA
Division of Cardiology
Cedars-Sinai Medical Center
Los Angeles, California, USA
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“There is a tendency to make the measurable important,
rather than the important measurable”
Robert S. McNamara
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Current Models for Benefit-Risk Assessment
• General models
Principle of Three, TURBO, etc., (not highly valuable)
• Simple models
Number needed to treat (NNT)/Number needed to harm (NNH)
or incremental net benefit (INB) that incorporate utility
functions, including patients preferences
• MCDA (Multi-criteria decision analysis)
The most sophisticated and highly valued model
• An ‘HTA-like’ model based on quality of life measures (QALYs), etc.
• Bayesian models
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Companies
• Purely qualitative (4/9)
• Semi-quantitative (4/9)
• Fully quantitative (1/9)
Agencies
• Purely qualitative (6/10)
• Semi-quantitative (4/10)
• Fully quantitative (0/10)
Low enthusiasm for quantitative approaches
Institute Study on the Current Status of Benefit-Risk
Assessment among Companies and Agencies
(N=9/23 pharma companies, 10/13 regulatory agencies)
Dr Neil McAuslane, Director of the Institute for Regulatory Science
CMR International, 2008
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Decision
Factor
Evidence and
Uncertainties
Conclusions and
Reasons
Analysis of Condition
Current Treatment Options
(unmet clinical need)
Benefits (efficacy from RCTs)
Risks (from RCTs, SAE reports)
Qualitative Framework for Benefit/Risk Analysis
FDA’s Five-Item Grid Proposal (PDUFA V)
“Qualitative science grounded in quantitative data and dependent upon judgment”
Risk Management (REMS)
Benefit Risk
Summary Assessment
http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM329758.pdf
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Strength
of evidence
Assessing Drug Safety Key Elements in Decision Making
Seriousness
& magnitude
of adverse
event
Safer
alternatives
& patient
preference
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Grading Importance of Outcomes
9
8
7
6
5
4
3
2
1
Critical (death, Q-MI, disabling stroke,
major bleeding)
Important, but not critical (recurrent ischemia, recurrent
hospitalization, restenosis / TVR,
silent /biomarker MI, groin hematoma)
Informative, but not important (surrogate markers: LDL, BS/A1C, BP,
CRP, PVCs, creatinine)
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How to Assess the Tradeoff Between Efficacy (Reduced Atherothrombotic Events) and
Safety (Increased Bleeding) of Vorapaxar?
• Subjectively assess separate analyses of safety and efficacy
- NNT vs NNH (favorable BR balance: NNT < NNH)
- Assumes equivalence of primary efficacy and safety endpoint
• A formal, weighted composite safety and efficacy endpoint
- Would require weights based on patient- and physician-determined
value judgments (difficult to assess; done a priori)
• Net clinical benefit analyses (NCO, NACE)
- Combines efficacy and safety into one composite endpoint
- Assumes each component is equivalent
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Endpoint Placebo Vorapaxar HR (95% CI) P value ARD NNT/
NNH (-)
Vorapaxar in Stabilized CAD & PAD (TRA 2OP) Benefit-Risk (BRAT) in Overall Cohort (N=26,449)
CVD/MI/Stroke/UCR (PEP) 12.4% 11.2% 0.88 (0.82-0.95) 0.001 1.2% 83
CVD/MI/Stroke (SEP) 10.5% 9.3% 0.87 (0.80-0.94) <0.001 1.2% 83
MI 4.8% 4.1% 0.85 (0.76-0.95) 0.005 0.7% 143
GUSTO Moderate/Severe
bleeding 2.5% 4.1% 1.67 (1.43-1.94) <0.001 -1.6% -63
Clinically significant
bleeding 11.1% 15.7% 1.46 (1.35-1.57) <0.001 -4.6% -22
Intracranial Hemorrhage 0.5% 0.9% 1.91 (1.36-2.69) <0.001 -0.4% -250
CVD/MI/Stroke/UCR/GUSTO
Moderate/Severe bleed
(NCO)
12.2% 11.7% 0.95 (0.89-1.02) 0.142 0.5% -
Benefit-risk balance not favorable for the overall cohort
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Vorapaxar in TRA 2OP Benefit-Risk in Proposed Label Population* (N=16,856)
Endpoint Placebo Vorapaxar HR (95% CI) P value ARD NNT/
NNH (-)
CVD/MI/Stroke/UCR (PEP) 11.4% 9.8% 0.82 (0.74-0.90) <0.001 1.6% 63
CVD/MI/Stroke (SEP) 9.0% 7.4% 0.78 (0.70-0.88) <0.001 1.6% 63
MI 5.3% 4.4% 0.83 (0.72-0.95) 0.005 0.9% 111
GUSTO Moderate/Severe
bleeding 2.0%
10.2%
3.0% 1.54 (1.24-1.90) <0.001 -1.0% -100
Clinically significant
bleeding 14.8% 1.48 (1.35-1.63) <0.001 -4.6% -22
Intracranial Hemorrhage 0.4% 0.5% 1.44 (0.87-2.40) 0.160 -0.1% -
CVD/MI/Stroke/UCR/GUSTO
Moderate/Severe bleed
(NCO)
11.5% 10.3% 0.89 (0.82-0.98) 0.017 1.2% 83
*History of MI and without prior stroke or transient ischemic attack (post hoc subset)
Benefit-risk balance favorable for proposed label population
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Vorapaxar in TRA 2OP Treatment Effect According to Eligibility Criterion
• Benefit driven by treatment effect in CAD stratum
• No heterogeneity of treatment effect in CAD and PAD strata
Population Enrollment
Criterion
Proposed
Label
Approved
Label
CAD stratum
(>2-52 wks post-MI) 0.83 (0.76-0.92) 0.82 (0.74-0.90) 0.82 (0.74-0.90)
CVD stratum 1.02 (0.84-1.23) No No
PAD stratum 0.95 (0.79-1.14) No 0.87 (0.71-1.06)
Overall 0.88 (0.82-0.95) 0.82 (0.74-0.90) 0.83 (0.76-0.90)
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Vorapaxar in TRA 2OP Benefit-Risk in Post-MI or PAD Patients Without
a History of Stroke or TIA (FDA Label, N=20,170)
Benefit-risk balance favorable for the cohort
Endpoint Placebo Vorapaxar HR (95% CI) ARD NNT
CVD/MI/Stroke/UCR (PEP) 11.8% 10.1% 0.83 (0.76-0.90) 1.7% 59
CVD/MI/Stroke (SEP) 9.5% 7.8% 0.80 (0.73-0.89) 1.7% 59
CV death 2.8% 2.4% 0.86 (0.71-1.03) 0.4% -
Myocardial Infarction 6.4% 5.4% 0.82 (0.73-0.93) 1.0% 100
Moderate/Severe bleeding 2.4% 3.7% 1.55 (1.30-1.86) -1.3% -77
Clinically significant bleeding 10.9% 15.5% 1.47 (1.35-1.60) -4.6% -22
Intracranial Hemorrhage 0.4% 0.6% 1.46 ( 0.92-2.31) -0.2% -
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Endpoint Placebo Vorapaxar HR (95% CI) P value ARD NNT/
NNH (-)
Vorapaxar in ACS (TRACER Trial) Benefit-Risk in Overall Cohort (N=12,944)
CVD/MI/Stroke/UCR (PEP) 19.9% 18.5% 0.92 (0.85-1.01) 0.072 1.4% -
CVD/MI/Stroke (SEP) 16.4% 14.7% 0.89 (0.81-0.98) 0.018 1.7% 58
MI 10.3% 9.2% 0.88 (0.78-0.99) 0.033 1.4% 71
GUSTO Moderate/Severe
bleeding 5.8% 7.6% 1.36 (1.18-1.57) <0.001 -1.9% -56
Clinically significant
bleeding 14.6% 19.5% 1.41 (1.29-1.54) <0.001 -4.9% -21
Intracranial Hemorrhage 0.4% 1.1% 2.52 (1.48-4.29) <0.001 -0.7% -143
Benefit-risk balance not favorable for the overall cohort
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Benefit-Risk Balance in TRA 2OP (Approved Label) 1000 Patients Treated with Vorapaxar Instead of Placebo
Vorapaxar vs placebo
Benefit
• 17 ischemic endpoints prevented
- 10 MIs
Risk
Clinical importance of MIs ? Fatal vs nonfatal
• 13 excess GUSTO Mod/Severe bleeds or
• 46 excess clinically significant bleeds - 12 GI bleeds
Clinical importance of Bleeds ? Q-wave vs non-Q wave MI ? Hospitalizations ? Heart failure/LVSD, arrhythmia, SCD ? Resource utilization
Does the evidence favor Class I (benefit >>> risk)
recommendation for vorapaxar in stabilized ACS/PAD?
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How is Bleeding Different from a MI? Variable Weights Based on Perception of “Utility”
CAD
MI risk Bleeding risk • MIs are part of the disease,
incompletely prevented by
therapy
• Can’t count the MIs that
are prevented
• All MIs are not created equal
(clinical importance varies)
• Spontaneous major bleeding
is unusual, bleeding
unequivocally caused by Rx
• Events are easy to count
• Bleeding causes panic
• Increased LOS and cost
Asymmetry in assessment of benefit-harm (bleeding > MI)
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How is Bleeding Different from a Stroke? Variable Weights Based on “Utility”
A Fib
Stroke risk Bleeding risk • Embolic strokes are part of
the disease, incompletely
prevented by therapy
• Can’t count the strokes that
are prevented
• Strokes usually associated
with long-term effects
• Spontaneous major bleeding
is unusual, bleeding
unequivocally caused by Rx
• Events are easy to count
• Bleeding causes panic
• Consequences are typically
finite
Asymmetry in assessment of benefit-harm (bleeding>>stroke)
Physicians: bleeding: stroke risk: 4:1
Patients: bleeding: stroke risk: 10:1
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Benefit-Risk in Drug & Device Development Asymmetry in Assessment of Efficacy & Safety
• RCTs • Anticipated, prespecified • Adequate power • Adjudicated • Precisely measured and
quantified (P values)
Efficacy • Non-clinical data, PK/PD studies,
meta-analyses, observational databases, AERS/Sentinel
• RCTs: limited exposure, narrow population
• Unanticipated, not prespecified • Not adjudicated (after the fact) • Delayed/late onset events
missed (after withdrawal) • Not precisely measured and
quantified (r/o unacceptable risk)
Safety
O’Neill RT, Drug Information Journal 2008;42;235–245
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Assessing Drug Safety Post-Approval Lessons from Vioxx, Avandia and Meridia
Characteristic Rofecoxib
(Vioxx)
Rosiglitazone
(Avandia)
Sibutramine
(Meridia)
Date of approval 5/20/1999 5/25/1999 11/22/1997
Approval outcome Pain control Glycemic control Weight loss
Indication - Osteoarthritis
- Acute pain in adults
- Dysmenorrhea
- Type 2 DM in
conjunction with
diet and exercise
- Obesity
BMI>30kg/m2
BMI>27kg/m2 + CRF
Warnings, precautions GI side effects,
renal disease Class III/IV CHF
Uncontrolled HTN,
CVD, CHF, arrhythmia
Post-marketing safety trial VIGOR
(N=8,076; 9m)
RECORD
(N=4,447)
SCOUT
(N=10,000; 3.8y)
Safety signal Excess CV risk ? CV risk Excess CV risk
Post-approval
regulatory action Withdrawn
9/29/2004
Restricted access
10/8/2010
Withdrawn
10/8/2010
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Meta-analysis
(N=10)
(+ 4 updates)
Prospective RCT
(N=1)
RECORD
Epidemiologic
(28 studies)
Rosi vs. con
Pio vs. con
Rosi vs. Pio
Post hoc/RCT
(N=3)
BARI-2D
ACCORD
VADT
Cardiovascular
Effects of
Rosiglitazone
• Large exposure (309 MACE)
• HR >1.3 r/o for all events except MI
• Favorable lean on mortality
• Burdened by study design and
conduct issues that preclude
reassuring estimates
• Inconsistent and fragile evidence
• Methodological limitations
• Results not reliable or replicable
• Good for raising questions, not settling them • Weak associations (OR<1.5-2.0)
• Confounding
• Prespecified hypothesis in 1 study
• MI risk not validated
• Hypothesis generating at best
• Post hoc nonrandomized
observations challenge
interpretability
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• ODE/CDER/FDA
• ACCF/AHA
• US FDA restricts marketing
No risk risk
• OSE/CDER/FDA
• ADA/EASD
• EMA suspends marketing
Rosiglitazone and Cardiovascular Events Divergence of Opinion
Insufficient evidence to either incriminate or exonerate rosiglitazone
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Regulatory Approval for Diabetes Therapies Primary Criterion: Glycemic Control (HbA1c)
• HbA1c and vascular risk - UKPDS: ↑ vascular risk when HbA1c >5.5% - ADVANCE: ↑ microvascular risk >6.5%: ↑ CVD risk >7.0%
• Intensive glycemic control (Type 1 DM) - Moderate quality evidence of microvascular benefit (DCCT x6.5y)
- Moderate quality evidence of macrovascular benefit (DCCT x6.5y
plus EDIC x10y)
• Intensive glycemic control (Type 2 DM) - Moderate quality evidence for microvascular benefit (UKPDS x10y)
- Low quality evidence for macrovascular benefit (UKPDS x20y)
- No evidence of micro or macrovascular benefit ( ACCORD,
ADVANCE, VADT)
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Treatment HbA1c Lipids Weight BS CHF CV event
Sulfonylureas ~1% +/- +/-
Metformin* ~1% LDL (10mg%) +/- +/- +/- ? (obese)
Acarbose ~0.5% +/- +/- ? +/- ?
Rosiglitazone** ~1% LDL, HDL TG +/- 2-fold ?
Pioglitazone** ~1% LDL, HDL,
TG +/- 1.5-fold ?
Nateglinide ~0.5% +/- +/- ? ?? ??
Repaglinide ~1% +/- +/- ?? ??
DPP-4 inhibitors ~1% ? +/- +/- ? No
GLP-1 agonists ~1% LDL, TG, HDL +/- ?? ??
SGLT2 inhibitor ~0.7% LDL, HDL,TG +/- ?? ?
Comparison of Oral Antidiabetic Therapies
*Lactic acidosis, GI side effects; ** fractures, macular edema (case reports), ? bladder cancer
Bolen et al, Systematic Review. Ann Int Med 2007;147:386-99; Ann Int Med 2011
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2008 FDA Diabetes Guidance Recommendations
• Primary evidence for regulatory approval: glycemic control
• Demonstrate that therapy will not result in an unacceptable increase in CV risk (noninferiority)
• Phase 2/3 design should permit a pre-specified meta-
analysis of major cardiovascular events (MACE)
• Independent committee should prospectively and blindly adjudicate MACE
• Trials should include patients at increased risk for cardiovascular disease (advanced CVD, CKD, elderly)
• Trial duration(s) should be longer than 3-6 months to obtain enough events and provide long-term data (~2yrs)
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116994.htm
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2008 FDA CVOT Guidance Ruling Out Excess CV Risk: Two-Step Approach
Trial “Reassuring” No. of Patient
phase Point Estimate Events Exposure
Screening
(Premarketing, Stage 1) <1.262 122 2500 x 2y
<0.91
<0.53
Premarketing 122 2500 x 2y
Pre- + post-
marketing* 122 2500 x 2y
Confirmatory
(Postmarketing, Stage 2) <1.11 611 6000 x 5y
*Using O’Brien-Fleming adjustment 0 1 1.3 1.8 2
Hazard ratio
Goal is to rule out 6 excess events/1000 PY from a baseline of 20 events/1000 PY
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-
Present Landscape of CVOT in Type 2 DM N~150K, 18 Trials (N~170K, 20 Trials)
CAROLINA Linagliptin 6000
CARMELINA Linagliptin 8300
TECOS Sitagliptin 14000
EXAMINE* Alogliptin 5380
NCT01703208 MK 3102 4000
EXSCEL Exenatide 14000
REWIND Dulaglutide 9622
LEADER Liraglutide 9340
SUSTAIN 6 Semaglutide 3297
ELIXA Lixisenatide 6000
ACE Acarbose 7500
GRAND 306 Fasiglifam 5000
DEVOTE Insulin Degludec 7500
DECLARE TIMI-58 Dapagliflozin 27000
CANVAS Canagliflozin 4335
CANVAS-R Canagliflozin 5700
CREDENCE Canagliflozin 3627
EMPA-REG OUTCOME Empagliflozin 7000
NCT01986881 Ertugliflozin 3900
Name of trial Drug Estimated enrollment SAVOR TIMI-53* Saxagliptin 18206
* Completed trial
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Potential CV Effects of DPP-4 Inhibitors Modeling Projection Based on Intermediate Outcomes
Alogliptin vs placebo
Benefit
• HbA1C (-0.36%) - HR 0.96 (-0.88% = HR 0.911)
• Weight loss (+0.06kg)
• BP lowering (neutral) 2
• Lipid profile (neutral) 3
Risk
• CHF signal (RR 1.19)4
Expected MACE benefit: 0.96 x 1.00 x 1.00 = 0.96
(4% risk reduction in MACE4 vs 19% risk increase in CHF4 ) 1Diabetologia 2009, 2BMJ 2009, 3CTT Meta-analysis, Lancet 2010, 4NEJM 2013
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Potential CV Effects of DPP-4 Inhibitors Modeling Projection Based on Intermediate Outcomes
Saxagliptin vs placebo
Benefit
• HbA1C (-0.20%) - HR 0.98 (-0.88% = HR 0.911)
• Weight loss (-0.50kg) - ? Impact on CV outcomes
• BP lowering (neutral) 2
• Lipid profile (neutral) 3
Risk
• CHF signal (RR 1.27)4
Expected MACE benefit: 0.98 x 1.00 x 1.00 = 0.98
(0% risk reduction in MACE4 vs 27% risk increase in CHF4 ) 1Diabetologia 2009, 2BMJ 2009, 3CTT Meta-analysis, Lancet 2010, 4NEJM 2013
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SGLT2 Inhibitors for Treatment of Diabetes
Balancing Benefits and Risks
SGLT2 inhibitors
Benefit
• Effective glycemic control
(-0.66% HbA1c c/w placebo)
• hypoglycemia (-SU, insulin)
• Weight loss (-1.8Kg)
• BP lowering (-4.5 mmHg)
Risk
• Mycotic genital infection (OR 5.0)
• UTI (OR 1.4)
• Polyuria, nocturia, dysuria
• Volume depletion, thirst, ↑ Hct
• Dyslipidemia (↑ LDL, non-HDL)
Uncertainty about CV & renal effects, bone health, malignancy
Adapted from Vasilakou et al, Ann Intern Med 2013;159;262-274
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GLP-1 Agonists for Treatment of Diabetes
Balancing Benefits and Risks
GLP-1 agonists
Benefit
• Effective glycemic control
(-0.6-1.0% HbA1c c/w placebo)
• hypoglycemia (-SU)
• Weight loss (-2.9kg)
• BP lowering (-3.6/-1.4mmHg))
• Lipid profile (improved)
Risk
• Heart rate (↑) • ↑ Hypoglycemia (+SU)
Uncertainty about CV effects, pancreatitis, malignancy
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Implications for Drug Safety As Seen Through Rosi-Colored Glasses
• Life cycle evaluations
Conditional approval contingent on demonstration of efficacy & safety in phase III/IV trials
• Regulatory authority
Empower FDA to “enforce” post-marketing studies, labeling changes, and stringent REMS
• Resource allocation
Increase FDA funding to develop comprehensive post-marketing surveillance
• Registration of clinical trials
• Approvable endpoint
Disease-oriented surrogate endpoint vs. patient-oriented health outcome benefit
• Analytical standards (Diabetes CV Guidance)
Ruling out an unacceptable harm should be driven by clinical relevance >> trial feasibility
Avoiding partial unblinding to preserve data confidentiality and trial integrity
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• Determine efficacy validly
• Detect risks prudently
• Do both in a timely and efficient way
Drug Approval Process Key Attributes
Is the drug development and approval
process meeting these goals?